Salivary cortisol in early psychosis: New findings and meta-analysis.

Schizophrenia is a multifactorial disorder and environmental risk factors for it might contribute to hypothalamo-pituitary-adrenal axis (HPA) dysregulation. While increased cortisol levels have been reported in schizophrenia, as well as in early psychosis (compared to healthy controls), a crucial unresolved issue is whether elevated cortisol levels could be related to the distress of an emerging illness, rather than being specific to psychosis. Here, we report new findings from the first French cohort of young help-seekers (ICAAR) including ultra-high risk subjects (UHR), first-episode of psychosis (FEP) and non at-risk help seekers controls (HSC), followed by a meta-analysis of all available reports on salivary basal cortisol levels in early psychosis (UHR and FEP). In the ICAAR study, 169 individuals (15-30 years old) had their basal cortisol levels sampled and they were categorized (at baseline) as either UHR, FEP, or HSC using the criteria of the Comprehensive Assessment of At-Risk Mental States (CAARMS). The three groups were compared at baseline, and the UHR and HSC individuals were also included in a one-year longitudinal follow-up. UHRs who converted to psychosis at the follow up (UHR-P) were compared to non-converters (UHR-NP). We also performed a meta-analysis from case-control studies with basal salivary measures of cortisol, drawing from a systematic bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'schizotypal ', 'prodromal schizophrenia', 'first-episode psychosis', 'first episode schizophrenia', 'newly diagnosed schizophrenia', 'recent onset schizophrenia' [in Medline, Web of Knowledge (WOS), EBSCO], followed by a systematic screening of the resulting articles. Basal cortisol levels were not significantly different between UHR, FEP, and HSC controls in the ICAAR cohort. Interestingly, initial cortisol levels were correlated with positive symptoms at the one year follow-up in the ICAAR cohort. The meta-analysis revealed a significant elevation of the salivary basal cortisol levels in UHR individuals compared to controls (8 studies--1060 individuals), but not between FEP and controls (6 studies--441 individuals). Indirect comparison of salivary basal cortisol levels between UHR and FEP did not yield significant differences. Finally, no differences were detected between the baseline cortisol of UHR-P and UHR-NP (4 studies--301 individuals). The meta-analysis (including new data) indicates that basal cortisol levels were increased in UHR compared to controls, but FEP levels were not different from UHR or controls. Many confounding factors could decrease the effect size in FEP especially medication intake. Taken together with our new results (which made use of help-seeker controls, and not merely healthy controls), the findings indicate that basal cortisol levels may not be a reliable biomarker for early psychosis. Further studies are needed to clarify the precise role of the HPA axis in psychotic conversion.

Chaumette B ，Kebir O ，Mam-Lam-Fook C ，Morvan Y ，Bourgin J ，Godsil BP ，Plaze M ，Gaillard R ，Jay TM ，Krebs MO ... -  《-》

[Stress and psychotic transition: A literature review].

Psychiatric disorders are consistent with the gene x environment model, and non-specific environmental factors such as childhood trauma, urbanity, and migration have been implicated. All of these factors have in common to dysregulate the biological pathways involved in response to stress. Stress is a well-known precipitating factor implicated in psychiatric disorders such as depression, bipolar disorder, anxiety, and possibly schizophrenia. More precisely, psychosocial stress induces dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and could modify neurotransmission, which raises the question of the involvement of stress-related biological changes in psychotic disorders. Indeed, the literature reveals dysregulation of the HPA axis in schizophrenia. This dysregulation seems to be present in the prodromal phases (UHR subjects for ultra-high risk) and early schizophrenia (FEP for first episode psychosis). Thus, and following the stress-vulnerability model, stress could act directly on psychotic onset and precipitate the transition of vulnerable subjects to a full-blown psychosis. The present paper reviews the literature on stress and onset of schizophrenia, with consideration for the causal role vs. associated role of HPA axis dysregulation in schizophrenia and the factors that influence it, in particular during prodromal and earlier phases. We also discuss different methods developed to measure stress in humans. We performed a bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'first episode psychosis', 'schizotypal', 'prodromal schizophrenia' in Medline, Web of Knowledge (WOS), and EBSCO completed by a screening of the references of the selected articles. Stress has been studied for many years in schizophrenia, either by subjective methods (questionnaires), or objective methods (standardized experimental protocols) with biological sampling and/or brain imaging methods. These methods have suggested a link between dysregulation of the HPA axis and psychotic symptoms both through abnormal basal levels of cortisol and flattened reactivity to social stress. Imaging results suggest indirect modifications, including abnormal pituitary or hippocampal volume. Several factors dysregulating the HPA axis have also been highlighted, such as consumption of drugs (i.e. cannabis), childhood trauma or genetic factors (such as COMT, or MTHFR variants). Psychological stress induces subcortical dopaminergic activation attributable to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is present in the prodromal phase (UHR) in patients who have experienced a first psychotic episode (FEP) and in siblings of schizophrenic patients. Stress dysregulation is a plausible hypothesis to understand the psychosis onset. The effect of stress on brain pathways could participate to the mechanisms underlying the onset of psychotic symptoms, both as a precipitating factor and as a marker of a predisposing vulnerability. This dysregulation fits into the gene x environment model: in subjects with genetic predispositions, stressful environmental factors can modify biological pathways implicated in psychiatric disorders, promoting the emergence of symptoms. However, many confounding factors obscure the literature, and further studies are needed in schizophrenic patients, UHR and FEP patients to clarify the precise role of stress in psychotic transition. Identification of stress biomarkers could help diagnosis and prognosis, and pave the way for specific care strategies based on stress-targeted therapies.

Chaumette B ，Kebir O ，Mam Lam Fook C ，Bourgin J ，Godsil BP ，Gaillard R ，Jay TM ，Krebs MO ... -  《ENCEPHALE-REVUE DE PSYCHIATRIE CLINIQUE BIOLOGIQUE ET THERAPEUTIQUE》

Sex differences in morning cortisol in youth at ultra-high-risk for psychosis.

Research suggests abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function play an important role in the pathophysiology of psychosis. However, there is limited research on the biological stress system in young people at ultra high risk (UHR) for psychosis. Morning cortisol levels are particularly relevant to study in this context, as these markers reflect HPA regulation. This is the first examination of sex differences in morning cortisol levels in UHR individuals. Twenty-eight UHR and 22 matched healthy control participants were assessed in respect to symptoms and had home-based collection of salivary cortisol over three time points in the morning. It was predicted that the UHR participants would exhibit lower morning cortisol levels and lower cortisol would be associated with greater symptomatology (i.e. higher positive, negative, and depressive symptoms). Additionally, sex differences in morning cortisol levels were explored based on recent evidence suggesting that sex differences may play an important role in the exacerbation of psychosis. While there were no group differences in morning salivary cortisol secretion, there was a sex by time interaction among UHR individuals, such that only UHR males exhibited flat cortisol levels across two hours after awakening, whereas UHR females had a pattern of cortisol secretion similar to healthy controls, even among medication-free individuals (F=6.34, p=0.004). Cortisol AUC (area under the curve) across the three time points had a trend association (medium effect size; r=0.34, p=0.08) with depressive, but not positive or negative, symptom severity. These results stress the importance of considering sex differences in the psychosis-risk period, as they improve understanding of pathogenic processes.

Carol EE ，Spencer RL ，Mittal VA 《-》

Stressor-Cortisol Concordance Among Individuals at Clinical High-Risk for Psychosis: Novel Findings from the NAPLS Cohort.

Whilst elevations in basal cortisol levels have been reported among individuals at-risk for psychosis, the extent to which this represents hyperresponsivity of the hypothalamic-pituitary-adrenal (HPA) axis to psychosocial stressors encountered in the natural environment is currently unclear. We aimed to examine stressor-cortisol concordance among youth at clinical high-risk (CHR) for psychosis in the North American Prodrome Longitudinal Study 2 (NAPLS 2) and the relationship with clinical outcome. At baseline, CHR (N = 457) and healthy (N = 205) individuals provided salivary cortisol samples and completed daily stressor, life event, and childhood trauma measures. CHR youth were categorised as remitted, symptomatic, progression of positive symptoms, or psychosis conversion at the two-year follow-up. Within-group regression models tested associations between psychosocial stressors and cortisol; standardised beta coefficients (Stβ) were subsequently derived to enable within-group pooling of effect sizes across stressor types. After adjustment for potential confounders, all CHR subgroups reported greater exposure to life events and daily stressors, and more distress in relation to these events, relative to controls. All CHR groups were also more likely to experience childhood trauma; only CHR converters, however, were characterised by elevated basal cortisol. Daily stressor distress was significantly associated with cortisol in controls (β = 0.60, 95% CI: 0.12-1.08) and CHR youth who converted to psychosis (β = 0.91, 95% CI: 0.05-1.78). In controls only, life event exposure was associated with cortisol (β = 0.45, 95% CI: 0.08-0.83). When pooled across stressors, stressor-cortisol concordance was substantially higher among CHR converters (Stβ = 0.26, 95% CI: 0.07 to 0.44) relative to CHR progressed (Stβ = 0.02, 95% CI: -0.11 to 0.15), symptomatic (Stβ = 0.01, 95% CI: -0.11 to 0.12), and remitted groups (Stβ = 0.00, 95% CI: -0.13 to 0.13); however, unexpectedly, healthy controls showed intermediate levels of concordance (Stβ = 0.15, 95% CI: 0.05 to 0.26). In conclusion, whilst all CHR subgroups showed increased psychosocial stress exposure and distress relative to controls, only those who later converted to psychosis were characterised by significantly elevated basal cortisol levels. Moreover, only CHR converters showed a higher magnitude of stressor-cortisol concordance compared to controls, although confidence intervals overlapped considerably between these two groups. These findings do not support the notion that all individuals at CHR for psychosis show HPA hyperresponsiveness to psychosocial stressors. Instead, CHR individuals vary in their response to stressor exposure/distress, perhaps driven by genetic or other vulnerability factors.

Cullen AE ，Addington J ，Bearden CE ，Stone WS ，Seidman LJ ，Cadenhead KS ，Cannon TD ，Cornblatt BA ，Mathalon DH ，McGlashan TH ，Perkins DO ，Tsuang MT ，Woods SW ，Walker EF ... -  《-》

Resting cortisol level, self-concept, and putative familial environment in adolescents at ultra high-risk for psychotic disorders.

A growing body of evidence suggests that resting cortisol levels are elevated in patients with schizophrenia and closely tied to symptom severity. However, there is limited research on the biological stress system during the ultra high-risk (UHR) period immediately preceding the onset of psychosis, and cortisol has not been examined in relation to individual characteristics such as self-concept or potential stressors such as putative familial environment in this critical population. In the present study, salivary cortisol samples were collected on 37 UHR and 42 matched control adolescents, and these individuals were assessed with clinical interviews as well as a measure of self-concept. For a subsection of the sample (23 UHR and 20 control adolescents), a participating relative/caretaker was also assessed with an expressed emotion interview designed to gauge psychosocial environment. Consistent with previous studies, UHR participants exhibited elevated resting cortisol levels when compared with controls. In addition, UHR adolescents exhibited increased negative self-concept and their relatives/caretakers endorsed significantly fewer initial positive statements about the participant. Interestingly, a strong trend in the UHR group suggests that higher cortisol levels are associated with higher rates of critical statements from relatives/caretakers. Furthermore, elevated cortisol levels in the participants were associated with increased negative self-concept as well as fewer initial positive comments from relatives/caretakers. Results suggest that hypothalamic-pituitary-adrenal axis (HPA) dysfunction is closely associated with both individual and environmental-level characteristics. Taken together, these findings support a neural diathesis-stress model of psychosis and future studies, designed to examine causal relationships, stand to inform both our understanding of pathogenic processes in the high-risk period as well as early intervention efforts.

Carol EE ，Mittal VA 《-》